Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis |
| |
| Authors: | Fengjie Huang Aihua Zhao Wenlian Chen Jingyu Yan Yunjing Zhang Sha Lei Kun Ge Xiaojiao Zheng Jiajian Liu Mingming Su Ping Liu Wei Jia |
| |
| Affiliation: | 1. Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China;2. Metabolomics Shared Resource, University of Hawaii Cancer Center, Honolulu, HI;3. E‐Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China;4. Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China |
| |
| Abstract: | Dysregulated bile acids (BAs) are closely associated with liver diseases and attributed to altered gut microbiota. Here, we show that the intrahepatic retention of hydrophobic BAs including deoxycholate (DCA), taurocholate (TCA), taurochenodeoxycholate (TCDCA), and taurolithocholate (TLCA) were substantially increased in a streptozotocin and high fat diet (HFD) induced nonalcoholic steatohepatitis‐hepatocellular carcinoma (NASH‐HCC) mouse model. Additionally chronic HFD‐fed mice spontaneously developed liver tumors with significantly increased hepatic BA levels. Enhancing intestinal excretion of hydrophobic BAs in the NASH‐HCC model mice by a 2% cholestyramine feeding significantly prevented HCC development. The gut microbiota alterations were closely correlated with altered BA levels in liver and feces. HFD‐induced inflammation inhibited key BA transporters, resulting in sustained increases in intrahepatic BA concentrations. Our study also showed a significantly increased cell proliferation in BA treated normal human hepatic cell lines and a down‐regulated expression of tumor suppressor gene CEBPα in TCDCA treated HepG2 cell line, suggesting that several hydrophobic BAs may collaboratively promote liver carcinogenesis. |
| |
| Keywords: | bile acids gut microbiota inflammation proliferation liver carcinogenesis |
|
|
